Lymphomatoid Granulomatosis: A Case Report and Literature Review of a Rare Pediatric Disorder From Pakistan.

BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare pediatric disorder driven by the Epstein-Barr virus and is considered as a part of the lymphoma spectrum. It is mostly associated with immune deficiency and patients on immunosuppressive therapy, especially with acute leukemia. It can present as a multisystemic disease, diagnosed on biopsy as atypical lymphocytes with an angiocentric pattern against a background composed of histiocytes, neutrophils, and extensive T-cell infiltration. OBSERVATION: We report 3 cases of children with Lymphomatoid granulomatosis, one with Langerhans cell histiocytosis. CONCLUSION: Combination chemotherapy was used for the treatment of Lymphomatoid granulomatosis; however, the prognosis is guarded. One of 3 patients is alive and in remission on the last follow-up visit at 15 months.

Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment. In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune modulation and combination immunochemotherapy, are discussed.

Mimickers of pulmonary lymphoma.

There are multiple entities that involve the lung that have radiographic, clinical, and morphologic overlaps with pulmonary lymphoma. In this review, we will discuss these entities in detail and provide relevant updates.

Lymphomatoid granulomatosis mimicking cancer and sarcoidosis.

Two cases of misdiagnoses of lymphomatoid granulomatosis are discussed here. Lymphomatoid granulomatosis is an Epstein-Barr virus-associated lymphoproliferative disorder with aggressive behavior. Due to its rarity and many presentations, delay in diagnosis and treatment is common. Its histological features including large atypical B-cells, T cell predominance, angiocentricity, necrosis, and evidence of EBV-positive cells should elicit the diagnosis of lymphomatoid granulomatosis. The settings that are described here have not yet been described in the literature.

EBV-Negative Cutaneous Lymphomatoid Granulomatosis With Concomitant EBV-Positive Pulmonary Involvement: A Potential Diagnostic and Prognostic Pitfall.

Lymphomatoid granulomatosis (LYG) is a rare, T-cell-rich Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder. Although LYG presents most often with lung involvement, up to half of affected individuals have concomitant cutaneous LYG. EBV-encoded RNA (EBER) is detected in the majority of pulmonary lesions but is often negative in skin lesions. Herein, we describe a case of concomitant EBV-positive pulmonary and EBV-negative cutaneous LYG in a 70-year-old woman. Histologically, both skin and lung biopsies demonstrated angiocentric necrosis with vascular wall compromise and a brisk inflammatory infiltrate comprised of plasma cells, histiocytes, and lymphocytes. Immunohistochemical studies on the skin biopsy demonstrated predominance of T cells and scattered B cells within the inflammatory infiltrate. Chromogenic in situ hybridization (CISH) for EBER was negative in the cutaneous infiltrate. The lung biopsy showed similar immunohistochemical findings but CISH for EBER demonstrated numerous EBV-positive B cells. Overall, this case demonstrates the variability of EBER positivity by CISH in multisystem LYG and underscores that its absence in cutaneous lesions does not exclude LYG from the differential diagnosis. Additionally, this case highlights the fact that cutaneous specimens should not be used in grading LYG by the World Health Organization criteria.

Angiocentric and intravascular lymphomas.

Under the generic diagnosis of angiocentric and intravascular lymphomas are included several subtypes of lymphomas histopathologically characterized either by the predominantly endovascular-endoluminal presence of neoplastic lymphocytes of B-T or NK/T cell origin, or by a pathologic process centered around a blood vessels secondarily infiltrated and invaded by the spreading infiltrate. This group of lymphoproliferative disorders is heterogeneous regarding phenotype, but they share common features that are multiorgan involvement, worse prognosis, and, frequently Ebstein-Barr virus (EBV) genomic integration. At onset, some of these rare lymphomas, e.g. intravascular large cell lymphoma or lymphomatoid granulomatosis (Liebow dieases), are misdiagnosed as inflammatory diseases. The actual treatments of these disorders are based upon chemotherapy and/or chemotherapy plus bone marrow transplantation with variable results. Therapeutic approaches for EBV related angiocentric and intravascular lymphomas, similarly to those employed for other viral induced lymphoproliferative disease would comprise the employment of chemotherapy together with drugs able to interfere with viral infection. Such an approach has been used in rare cases of EBV-positive diffuse large B-cell lymphoma of the elderly, a lymphoproliferative disorders which development is linked to immunosuppression due to senescence. The present review will focus on intravascular and angiocentric lymphomas providing histopathologic, immunophenotypical and molecular data useful to overcome to a specific diagnosis and to differentiate them from other lymphoproliferative disorders showing a secondary vascular engulfment and infiltration and some vasculitides showing overlapping histopathologic features.

Childhood lymphomatoid granulomatosis: a report of 2 cases and review of the literature.

Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a high-grade B-cell lymphoma protocol is justified.

An eschar and violaceous nodules as the presenting signs of lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder associated with infection by Epstein-Barr virus (EBV). The lung is the most common site of involvement, but LYG may initially manifest in the skin. LYG has been associated with immune dysregulation. Treatment regimens are not well-defined, but clinical trials targeting EBV have been successful. We report a 31-year-old male with LYG who presented with cutaneous symptoms. The skin biopsy was devoid of B-cells and non-reactive for EBV. We present this case to emphasize the role of dermatologists in the diagnosis of LYG and to caution clinicians that cutaneous lesions may lack diagnostic evidence of EBV infection.

[Methotrexate-related lymphomatoid granulomatosis successfully treated with discontinuation of methotrexate and radiotherapy to brain].

A 70-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) complained of right arm weakness. On CT and MRI, tumors were found in the right frontal lobe, bilateral lungs, and left renal parenchyma. She was diagnosed as having lymphomatoid granulomatosis (LYG) grade 2 on thoracoscopic biopsy of the left lung. We discontinued MTX and treated a mass lesion in the right frontal lobe with stereotactic radiotherapy. As a result, the tumors showed a gradual reduction in size, and the patient achieved complete remission. LYG is a rare lymphoproliferative disorder, and has various clinical characteristics. We describe herein a patient with LYG grade 2 with cerebral, pulmonary, and renal lesions, who has maintained a complete remission for six months, to date, after treatment.

[Lymphomatoid granulomatosis - the past and present]. / Lymfomatoidní granulomatóza - minulost a soucasnost.

BACKGROUND: Lymphomatoid granulomatosis (LyG) is a rare multisystemic angiocentric and angiodestructive B lymphoproliferative disease that was first described by Liebow in 1972. Disease was then in the "gray zone" between vasculitis and lymphoproliferative disease. LyG is currently categorized as a primary B lymphoproliferative disease associated with Epstein-Barr (EB) virus according to the World Health Organization (WHO) classification of tumours. EPIDEMIOLOGY, CLINICAL COURSE AND TREATMENT: Lymphomatoid granulomatosis is a rare disease with unknown prevalence. It occurs more often in males (male : female ratio 2 : 1) between the 5th to 6th decade of life and is more frequent in Europe than in Asia. Lungs are typically the predominantly affected organ; the disease spreads predominantly by extralymphatic manner. Spleen and lymph nodes are affected at an advanced stage. The clinical features are often nonspecific. Dyspnea, cough, hemoptysis, chest pain are the most common features with/without B symptoms (fever, night sweats, weight loss) in the pulmonary involvement. The radiographic finding of the lung is very diverse, but when there are multiple bilateral nodular lesions with basal predominance in perilymphatic distribution, we should think of this disease, although LyG rarely occurs. The histopathologic examination of affected tissue (most commonly the lung) is necessary to confirm the diagnosis. The thoracoscopy is used mainly. When the pulmonary findings are without any response to antibiotics, the autoimmune cause and other granulomatous inflammations (tuberculosis, sarcoidosis, etc.) are excluded, this diagnostic performance is indicated. Prognosis is variable - from spontaneous remission to progressive disease, often with aggressive behavior. Median survival is 14 months from diagnosis and mortality rate is 60% in the first year - despite the treatment. Treatment strategy is chosen depending on the histological grade. The therapy is not yet standardized. Interferon α, rituximab, glucocorticoids, cyclophosphamide and combined immunochemotherapy have been used for the treatment. The disease may lead to pulmonary failure, fatal CNS (central nervous system) involvement and sometimes develops into progressive EB virus positive lymphoproliferative disorder. CONCLUSION: Improvements in understanding of the biology of LyG, especially in determining the precise role of EB virus infection in its pathogenesis may lead to optimization of treatment strategies for this disease. Novel treatment modalities are urgently needed due to unfavourable prognosis. Adoptive immunotherapy appeals to be a promising approach.

Lymphomatoid granulomatosis mimicking PJP infection.

A male patient in his 40s who had been unwell for months with fever of unknown origin and clinicopathological features suspicious for haemophagocytic lymphohistiocytosis presented to hospital with worsening subacute shortness of breath. CT pulmonary angiogram demonstrated ground glass changes involving all lung lobes with an apicobasal gradient. These changes, combined with long-term steroid exposure for granulomatous hepatitis without pneumocystis prophylaxis, raised concern for pneumocystis jirovecii pneumonia (PJP). A subsequent bronchoscopic lavage specimen was positive on PCR for PJP and the patient was started on appropriate therapy. Clinical and radiological changes initially improved but after completion of therapy, symptoms and radiological abnormalities returned. Retreatment with second-line treatment resulted again in initial improvement followed by relapse with acute deterioration. Further investigations for an alternate diagnosis were made, with a surgical lung biopsy performed finally revealing immunosuppression-related Epstein-Barr virus positive large B cell lymphoma with lymphomatoid granulomatosis of grade 3 pattern.

Pulmonary lymphomatoid granulomatosis in a patient with long-term use of a tumour necrosis factor-α inhibitor.

A man in his 60s presented with intermittent constitutional symptoms along with waxing and waning chest radiographic abnormalities, eventually leading to a diagnosis of lymphomatoid granulomatosis (LYG). LYG is a rare, progressive Epstein-Barr virus (EBV)-driven lymphoproliferative disease associated with immune dysregulation most commonly involving the lungs. The diagnosis requires tissue biopsy; thus, the decision to pursue tissue sampling with histopathology examination in a timely manner is essential. Currently, there are no established guidelines regarding the treatment of LYG, which varies from cessation of immunosuppressants to immunochemotherapy and usually requires multidisciplinary team discussion.

Acute respiratory failure developing in a patient with lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare B cell lymphoproliferative disorder associated with Epstein-Barr virus infection. LYG diagnosis is often difficult because of non-specific and varied radiological and pathological findings. The lung is the most common organ of LYG occurrence, but extrapulmonary lesions involving the central nervous system, skin, kidneys and liver are observed. A surgical biopsy is often inevitable for LYG diagnosis.We encountered a man in his 50s who presented with progressive dyspnoea. Extrapulmonary lesions were not observed. Although he developed respiratory failure within a short period, a low dose of corticosteroid relieved his symptoms. Video-assisted thoracoscopic lung biopsy revealed grade 1 LYG. The patient was successfully treated with chemotherapy, including rituximab. Only a few cases of LYG with progressive respiratory failure are reported, and most have been diagnosed via autopsy. Our case highlights the importance of performing a surgical lung biopsy at the appropriate time to diagnose LYG.

Current histological diagnosis of lymphomatoid granulomatosis.

The current histological criteria for the diagnosis of lymphomatoid granulomatosis (LYG) are reviewed and summarized. The majority of patients present with multiple bilateral nodules involving the lung. Key histologic features necessary for the diagnosis include a mixed mononuclear cell infiltrate that shows vascular infiltration, appreciable numbers of T-cells, and variable numbers of CD20-positive B cells that show positivity for EBER by in situ hybridization.

Unique presentation of testicular involvement in lymphomatoid granulomatosis.

BACKGROUND: Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder associated with Epstein-Barr virus infection. It predominantly affects the lungs, skin, liver, kidneys, spleen, and central nervous system. Testicular involvement has never previously been described. The authors present the first documented case of testicular involvement in lymphomatoid granulomatosis. CASE REPORT: A 55-year-old gentleman with confirmed lymphomatoid granulomatosis on lung biopsy was noted to have a swelling in his scrotum. Ultrasound scanning demonstrated multiple ill-defined areas of reduced echogenicity throughout both testes with evidence of increased vascularity. Biopsy of the testis confirmed the presence of lymphomatoid granulomatosis. The patient was commenced on alpha-interferon therapy. However, marked clinical improvement occurred only following addition of high-dose oral corticosteroid approximately 1 week later. This resulted in resolution of the testicular swelling and his other symptoms. CONCLUSION: Prognosis with lymphomatoid granulomatosis depends mainly on grade. Our patient responded well to therapy but will continue to be closely followed up in the outpatient setting.